Exosomes from bipolar disorder patients induce mania- and depression-like behaviors in mice via shared and distinct neuroimmune signatures.

Bipolar disorder (BD) is a recurrent illness characterized by alternating episodes of mania and depression, yet the biological mechanisms underlying these oscillating states remain poorly understood. Exosomes, nanosized extracellular vesicles that mediate peripheral-central communication through transfer of molecular cargo, have emerged as important regulators of brain function and disease. To test whether patient-derived exosome preparations encode phase-specific signals, we isolated serum exosomes from BD patients experiencing manic or depressive episodes and infused them stereotaxically into the medial prefrontal cortex of mice. Behavioral assessments revealed strikingly divergent effects: mania-derived exosomes produced hyperlocomotion, reduced immobility, and heightened sociability, whereas depression-derived exosomes induced hypoactivity, anhedonia, and social withdrawal. Healthy control exosomes produced no changes, underscoring disease specificity. Despite these behavioral contrasts, both mania- and depression-derived exosomes convergently disrupted neural homeostasis, as indicated by oxidative and inflammatory imbalance, glial activation, synaptic impairments, and broad transcriptomic changes in pathways related to immune signaling, oxidative stress, and neuroplasticity. Importantly, phase-dependent patterns also emerged: mania-derived exosomes biased microglia toward a pro-inflammatory profile, whereas depression-derived exosomes favored an alternative polarization state with enrichment of metabolic and neurotrophic signaling. Pharmacological suppression of microglial activation attenuated the mania-exosome phenotype, supporting the functional involvement of M1-associated microglial activation in the mania condition. Integrative exosomal miRNA and transcriptomic analyses further identified miR-629-5p as a candidate mania-enriched cargo, and in vivo inhibition of miR-629-5p attenuated the associated behavioral and molecular abnormalities. Together, these findings show that serum-derived exosome preparations from BD patients are sufficient to induce mood-state-relevant behavioral and neurobiological changes under the experimental conditions tested, while the endogenous relevance of exosome-mediated signaling in spontaneous mood transitions remains to be established.